PROJECT SUMMARY Control of gene expression holds great promise for genome biology research and also as a new strategy for better treatment of human diseases caused by dysfunction of genes. However, currently, we lack a technology that is capable of modulating gene expression at the level of transcription in a reversible manner. Notably, recent advances in epigenetics have greatly enhanced our understanding on how site-specific chemical modifications in DNA-packing histones control gene expression in response to physiological and environmental stimuli. Specifically, in our own research, we have discovered a novel viral mechanism that controls host gene transcription through histone methylation. We show that chlorella virus uses a viral protein (termed vSET) to modify histone H3 at lysine 27 (H3K27) in the infected cells, thereby shutting down host transcription. Consistent with the fact that H3K27 methylation is a conserved epigenetic mark for gene transcriptional silencing in metazoa, vSET can effectively suppress gene transcription normally targeted by the Polycomb group proteins in human cells. Given its high selectivity for H3K27 methylation, vSET could in principle be developed into a highly selective epigenetic gene silencing technology by fusing to a gene-specific DNA binding domain. In this study, we will engineer vSET into a new gene transcriptional silencing technology and explore its great potential as a new epigenomics tool through characterizing vSET activity in controlling transcriptional repression of Polycomb target genes, and studying epigenetic functions of the Polycomb repressive complex proteins in cells.